CGRP and the structurally
related peptide adrenomedullin (AM) have profound depressor effects on
blood pressure, which are thought to be mediated through receptors composed
of G-protein-linked calcitonin receptor-like receptors (CL) with receptor
activity-modifying proteins (RAMP; McLatchie et al. 1998). Although the
hypotensive effects of exogenous CGRP and AM have been well characterised
in many species, to date there have been no such studies reported in the
mouse. In the present study, the hypotensive effects of exogenous CGRP
and AM were assessed and compared side-by-side in naturally ventilated
CD1 mice, anaesthetised with urethane (2.5mg/g, i.p.). Drugs were administered
as a bolus injection (100µl) into the jugular vein and consequent
effects on blood pressure were monitored via a cannula (OD<0.7mm) that
was inserted into the carotid artery and connected to a blood pressure
transducer and PowerLab data acquisition system.

Baseline mean arterial
pressure was 53 ± 5mmHg (n=7). Both CGRP and AM produced dose-dependent
decreases in blood pressure (Figure 1) with similar latencies for maximal
effect (~2min) and duration of action (~10min). Although CGRP proved to
be approximately 100 fold more potent than AM (ED50=3.2pmol
for CGRP compared with 345pmol for AM), the maximal depressor effect for
CGRP was lower than that for AM (% hypotension from baseline, 19.1 ±
2.9 for CGRP compared with 27.7 ± 1.6 for AM). When 2 repeated
injections of a single dose of either CGRP (10pmol) or AM (1000pmol) were
administered, the second response to CGRP was identical to the first,
even when the injection interval was as small as 15 min. In contrast,
the second response to adrenomedullin was attenuated compared with the
first response for at least a 3 h.

These data demonstrate
the dose-related ability of exogenous CGRP and AM to act as hypotensive
agents in the mouse. In addition these data further highlight differences
in the nature of the hypotension evoked by CGRP compared with AM. Future
studies will focus on characterising the receptors that mediate these
responses through use of available antagonists for CGRP (CL/RAMP1) and
AM1(CL/RAMP2) receptors as well as genetically
modified mice.